Contribution To Literature:

The PIONEER 6 trial showed that the cardiovascular risk profile of oral semaglutide was noninferior to placebo.

Description:

The goal of the trial was to evaluate oral semaglutide (glucagon-like peptide-1 [GLP-1] receptor agonist) compared with placebo among patients with type 2 diabetes at high cardiovascular risk. Safety has been established for subcutaneous semaglutide, but not for oral semaglutide.

Principal Findings:

The primary outcome, cardiovascular death, myocardial infarction, or stroke, occurred in 3.8% of the semaglutide group compared with 4.8% of the placebo group (p for noninferiority < 0.001; p for superiority = 0.17).

Adverse event leading to permanent discontinuation of study medication: 11.6% with semaglutide vs. 6.5% with placebo; mostly due to gastrointestinal effects in 6.8% with semaglutide vs. 1.6% with placebo

Interpretation:

Among patients with type 2 diabetes, oral semaglutide was noninferior to placebo in terms of cardiovascular safety. GLP-1 receptor agonists appear to have a favorable cardiovascular safety profile (lixisenatide and exenatide) or cardiovascular benefit (liraglutide, albiglutide, and semaglutide, dulaglutide), and this trial provides further evidence in that regard. Exenatide had been associated with acute kidney injury, presumably from nausea, vomiting, and diarrhea. All GLP-1 receptor agonists appear to be associated with increased gastrointestinal symptoms.